Neuropathic pain is a chronic disabling condition. Opiate drugs can be effective in treatment of neuropathic pain, but continuous administration of these drugs is complicated by the development of tolerance to analgesia and by dependence which results in an unpleasant withdrawal syndrome. Preventing the transition from drug use to drug tolerance/withdrawal has important clinical implications. Accumulating evidence suggests that neuropathic pain, chronic morphine tolerance and withdrawal-evoked hyperalgesia may be mediated through changes of proinflammatory cytokines, the phosphorylation of mitogen-activated protein kinases (MARK) and prostaglandin E2 (PGE2) in the spinal cord. We have demonstrated that highly defective herpes simplex virus (HSV)-based vectors can be used to efficiently transduce neurons of the dorsal root ganglion (DRG) in vivo to release bioactive peptides from nerve terminals in spinal cord. We will test the hypothesis that reduction of the inflammatory response by HSV vector-mediated release of the anti-inflammatory cytokine, interleukin-4 (IL-4) will decrease morphine tolerance and physical withdrawal in animals with neuropathic pain. Two specific aims are porposed: (1) To determine whether transgenemediated IL-4 release decreases morphine tolerance and physical withdrawal and (2) To investigate the effect of transgene-mediated IL-4 on neurochemical changes in spinal level during morphine tolerance and withdrawal. These studies will provide insight into role of proinflammatory cytokines in chronic morphine tolerance and withdrawal and important preliminary data that could serve as the basis for a subsequent grant application for junior principal investigator in this field.